Assessment of TDR’s Contributions to Product Development€¦ · Assessment of TDR’s Contributions to Product Development for Tropical Diseases: The Case of Ivermectin for Onchocerciasis

Assessment of TDR’s Contributions to Product Development for Tropical Diseases:

The Case of Ivermectin for Onchocerciasis

A Report Prepared by

Tomoko Fujisaki and Michael R. Reich Takemi Program in International Health

Harvard School of Public Health

February 12, 1997

Prepared for the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)

for the Third External Review of the Programme Activities

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Table of Contents Introduction ................................................................................................ 1 1. Problems ................................................................................................. 2 2. Activities and Major Players..................................................................... 3

2.1 Discovery ......................................................................................... 4

2.2 Clinical Trials .................................................................................... 7

2.3 Registrations ..................................................................................... 10

2.4 Production ........................................................................................ 12

2.5 Pricing .............................................................................................. 12

2.6 Distribution ....................................................................................... 15

2.7 Program Implementation ................................................................... 18 3. Conclusions ............................................................................................. 20

Figure and Tables Figure 1 Allocation of Annual TDR Filariasis Budget to Antifilarial Drug

Screening System, and to Development of Ivermectin for Onchocerciasis and Lymphatic Filariasis

Table 1 Number of Ivermectin Treatments by Year of Application Approval

(September 1988-1995) Table 2 Contributions of Major Actors to Ivermectin Development

Annexes Annex I Major Publications of Clinical Trials and Operational Research of

Ivermectin for Human Onchocerciasis Annex II Onchocerciasis-Endemic Countries and Ivermectin Treatment Programs Annex III Non-Governmental Organizations Involved in Ivermectin Treatment

Programs

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INTRODUCTION Onchocerciasis, also known as river blindness, is a chronic filarial disease caused by the worm Onchocerca volvulus. The disease is transmitted by the bite of infected female blackflies of the genus Simulium, which breed in highly oxygenated, fast-flowing rivers. The female worm discharges millions of microfilariae for some 10-14 years, which migrate through the skin, causing an intense pruritic rash, altered pigmentation, edema, and atrophy of the skin.1 Microfilariae often reach the eye, which results in loss of vision. In fact, onchocerciasis is the second leading cause of blindness due to an infectious disease. There are 34 countries where onchocerciasis is endemic: 27 countries of which are in Africa; 1 country in the Arabian peninsula (Yemen); and 6 countries in the Americas (Brazil, Colombia, Ecuador, Guatemala, Mexico, and Venezuela). In 1993, the WHO Expert Committee on Onchocerciasis Control estimated that about 17.7 million people were infected worldwide, of whom some 270,000 were already blind, and another 500,000 people were severely visually disabled.2 The burden of onchocerciasis is particularly heavy in the hyper-endemic belt across sub-Saharan Africa. In these communities, high rates of visual disability caused by onchocerciasis, up to 40% in some areas, often lead to declines in economic capacity, and eventual abandonment of fertile agricultural lands. Since 1987, ivermectin (22,23-dihydroavermectin B1) has been the drug of choice for the treatment of onchocerciasis because of its strong microfilaricidal effects and the absence of severe side effects. A single annual dose of 150 µg/kg of ivermectin given orally can reduce the level of skin microfilariae to near zero and, by virtue of its interference with embryogenesis, can delay build-up of microfilariae for a period of 3 months to 2 years. Ivermectin is produced under the registered trademark “MECTIZAN®” by Merck & Co., Inc., New Jersey, U.S.A., and donated by the company for onchocerciasis treatment in endemic countries. This report reviews the contributions made by the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) in the development of ivermectin. Particularly, it aims at identifying:

1. TDR’s major contributions in the different stages of the development of ivermectin;

2. Major factors that fostered or hindered TDR’s contributions; and 3. Implications of these assessments for TDR’s mandate in drug development for

tropical diseases. The report is divided into three parts. First, the report examines how TDR defined the problems that it sought to resolve for onchocerciasis control. Second, the

1 Benenson, AS. (Ed.) Control of Communicable Diseases in Man: An Official Report of the American

Public Health Association (Fifteenth Edition). 1990. 2 WHO Expert Committee on Onchocerciasis Control. Onchocerciasis and its Control. 1995.

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development process of ivermectin is reviewed to identify major activities that were carried out by TDR. The development process is divided into seven stages, and TDR’s activities are examined at each stage, along with TDR’s interactions with other actors. Third, major findings about TDR’s contributions to ivermectin development are discussed. Particular attention is given to conditions that existed during the development process, in order to highlight implications for TDR’s future activities in product development for tropical disease control. Information for this report was collected through a review of published and unpublished documents, as well as interviews with key persons who were involved in the development process.

1. PROBLEMS In the mid-1970s, TDR recognized onchocerciasis as a major public health problem affecting some 20-40 millions of people in endemic areas. The TDR Position Paper on Filariasis stated in 1976 that “above all, the menace of onchocerciasis lies in its ability to attack the eyes. River blindness is the endemic disease causing the highest rates of blindness in the world. Onchocerciasis is the only blinding disease which, by itself, is capable of halting the economic life of the communities affected. It may bring about desertion of good agricultural land near rivers, which is often the most fertile land available to communities living at bare subsistence level.”3 TDR identified the following six areas that required further research for the control of onchocerciasis:

1. Chemotherapeutic research; 2. Immunology and pathology; 3. In vitro culture of filarial parasites; 4. Animal models; 5. Epidemiology; 6. Ecology and environmental control.4

Research for effective and safe chemotherapeutic agents was considered to be of highest priority. At the time of TDR’s establishment in 1975, there were two drugs available for treatment of onchocerciasis: diethylcarbamazine (DEC) and suramin. Both of these drugs had serious problems associated with their clinical use:

DEC, which kills only the microfilariae of O. volvulus, excites violent and even dangerous hypersensitivity reactions in the human host. Suramin, developed 50 years ago for the treatment of sleeping sickness, is still the only drug whose use can be considered for killing the adult O. volvulus worms. It is a compound toxic in its own right and, in some patients with onchocerciasis, suramin may cause severe, dangerous, and occasionally

3 TDR. Position Paper on Research in Filariasis. 1976 (TDR/WP/76.10) p.5. 4 TDR. Position Paper on Research in Filariasis. 1976 (TDR/WP/76.10), pp. 8-9.

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fatal reactions. The parasitological cure of a patient with onchocerciasis, using DEC and suramin, demands some three months of treatment under medical supervision. Thus we have no drug available that can be used on a large scale to interrupt the transmission of O. volvulus by destroying the reservoir of the parasite in man5.

Therefore, the TDR Scientific Working Group (SWG) decided that the top priority for onchocerciasis chemotherapeutic research should be the discovery of new and non-toxic macrofilaricides effective against adult worms of O. volvulus. In order to achieve this goal, the SWG established the following six strategies in 1976:

a) Strengthening the activities of those few academic centers where compounds can be screened at the primary and secondary levels for basic filaricidal action;

b) Increasing the degree of cooperation from the pharmaceutical industry to release more compounds for screening;

c) Stimulating the rational synthesis of new groups of chemicals that might have filaricidal action;

d) Increasing basic knowledge of the metabolism of filarial parasites; e) Establishing a tertiary screening system, possibly using cattle; f) Toxicity tests, and pre-clinical and clinical trials.6

TDR thus defined the main problem as identifying an effective and safe chemotherapeutic agent that would kill adult worms of O. volvulus.

2. ACTIVITIES AND MAJOR PLAYERS The present analysis divides the ivermectin development process into seven stages: discovery; clinical trials; registration; production; pricing; distribution; and program implementation. While all stages are essential steps for successful product development, each stage involves different types of activities that require special sets of skills and resources. In this section, we review the major activities carried out by TDR, and examine what TDR contributed to the development of ivermectin at each stage. TDR’s activities are also discussed in relation to other major actors, including: Merck & Co., Inc. (referred to as Merck hereafter); the Onchocerciasis Control Programme in West Africa (OCP); academic institutions; the Mectizan Expert Committee; other organizations of the United Nations, such as the World Bank; NGOs; and governments of developing countries. 2.1 Discovery

5 TDR. Position Paper on Research in Filariasis. 1976 (TDR/WP/76.10) 6 TDR. Position Paper on Research in Filariasis. 1976. (TDR/WP/76.10)

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TDR contributed indirectly to the discovery of ivermectin’s antimicrofilarial activity through TDR’s recognition of the need for a viable screening system for filaricidal agents. At the first meeting of the Filariasis Scientific Committee in 1977, TDR reported that, after visits to 16 major pharmaceutical companies, none was actively working on onchocerciasis, nor was there a validated biological model for screening. The Scientific Committee agreed that the high costs required to maintain screening facilities for drugs against tropical diseases was one of the main factors hampering the industry’s active interest.7 At that time, there was a view within TDR that screening of new therapeutic agents through TDR-supported facilities would be a form of “assistance” to the pharmaceutical industry.8 Thus, TDR not only recognized that a screening system was a crucial bridge that was missing from the envisaged process of finding effective and safe macrofilaricides, but also saw its role to fill that gap. From 1977 on, TDR provided technical and financial support to establish a biological screening system for macrofilaricides. TDR identified five academic and private research institutions that had technical capacities and facilities for primary and secondary screens: the University of Georgia (USA), University of Giessen (Germany), Wellcome Foundation (United Kingdom), London School of Hygiene and Tropical Medicine (United Kingdom), and University of Tokyo (Japan). Between 1977 and 1988, TDR provided a total of nearly $2,250,000 to these five institutions for the primary and secondary screening of about 7,500 compounds in its search for compounds with potential filaricidal activity.9 Similarly, TDR established a tertiary screen with cattle, for compounds with positive results in the secondary screen, at the James Cook University of North Queensland, Australia, which received $434,880 between 1977 and 1988. This cattle screen became the best predictor of what a tested compound would do in human onchocerciasis and the screen’s validation by TDR contributed to a rationalization of the screen program. As TDR was setting up this international screening network for a filariasis drug, it also approached pharmaceutical companies to release existing compounds from their shelves for the purpose of screening against O. volvulus. In order to stimulate the industry’s cooperation, TDR assured protection of confidentiality for individual companies by receiving compounds only with a company’s code number, instead of chemical names. It was a “calculated risk” that TDR decided to take in order to collect as many compounds as possible, even though a company might choose not to develop a compound as a drug for onchocerciasis treatment, despite evidence of antifilarial activity in the screening system.10

7 TDR. Participation of the Pharmaceutical Sector. 1976. (TDR/WP/76.30) p. 2. 8 For example, see the meeting report of the Technical Review Group, Geneva, 23-28 September, 1976

(TDR/TRG/WP/76.3, p.14). The Group was set up to provide an independent review of TDR’s priorities, and consisted of 20 international experts and national health officials.

9 Report of the sixth meeting of the Scientific and Technical Advisory Committee (STAC-6), Geneva, 2-5 April 1984. (TDR/STAC-6/84.3)

10 Interview No. 5 with a TDR official (September 12, 1996).

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Ivermectin came into TDR’s screening system in 1978. However, its discovery goes back to 1975, when novel macrocyclic lactones, named avermectins, were found during routine biological screens by the Merck Sharp & Dohme Research Laboratories (MSDRL, now the Merck Research Laboratories) in Rahway, New Jersey, USA. These compounds presented an unprecedented spectrum of activity against parasites in animals at extremely low concentrations. Merck developed derivatives of avermectins to enhance the antiparasitic activity. Among these avermectin analogues, ivermectin was selected for further commercial development, and was found to be active against both ecto- and endoparasites in cattle, swine, horses and companion animals, and to have better toxicological features than other analogues.11 Ivermectin was introduced to the veterinary market in 1981, and has subsequently brought Merck huge commercial success. According to Merck’s annual report of 1995, ivermectin was the world’s largest-selling animal health product with more than 5 billion doses sold worldwide even after almost 15 years in the market. The report also stated that the group of ivermectin-based parasiticide products was the fifth best-selling product group for Merck (including human drugs) with $740 million annual sales.12 The life of ivermectin as a human drug began in April 1978 when Merck scientists, under the direction of Dr. William C. Campbell, observed that the drug was effective against microfilariae of Onchocerca cervicalis in horses. O. cervicalis in horses belongs to the same genus as O. volvulus, the cause of onchocerciasis in human. In July 1978, Dr. Campbell sent ivermectin and the results of the horse trial to the TDR-supported tertiary screening facility using cattle in Australia. The results showed that ivermectin was “highly effective in preventing patent infections with both O. gibsoni and O. gutturosa,” and thereby added evidence to the expectation that ivermectin would be effective against human onchocerciasis.13 On December 20, 1978, encouraged by these results, Dr. Campbell proposed to the MSDRL Research Management Council that “an avermectin could become the first means of preventing the blindness associated with onchocerciasis” and that “discussions be held with representatives of WHO to determine the most appropriate approach to the problem.”14 The senior management of MSDRL was supportive of the lead taken by Dr. Campbell, and research funding to investigate the potential use of ivermectin in humans was approved by Dr. Roy Vagelos, then the president of MSDRL, in December 1978. On January 16, 1980, Merck’s senior management decided to proceed independently to Phase I trials. The decision was a significant turning point in the history of ivermectin, in that it shaped the course of events over the next eight years. While excitement was building up inside Merck for the prospect of a new drug for human onchocerciasis, TDR’s reactions to the initial data about ivermectin were less enthusiastic between 1979 and 1982. In February 1979, the TDR Scientific Working Group on Filariasis received the report on the screening results of ivermectin, but Merck 11 Sutherland, IH. Veterinary use of ivermectin. Acta Leidensia. 1 and 2: 211-216, 1990. 12 Merck & Co., Inc. Merck Annual Report, p.5 and p.20, 1995. 13 TDR. Report of the Scientific Working Group on Filariasis for 1980-83, p.22. 14 Sturchio, J. The Decision to Donate MECTIZAN: Historical Background, 1992. Unpublished

manuscript, distributed by Merck, and an interview No. 15 (October 7, 1996).

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did not receive any reaction from TDR. In October 1979, a TDR official visited Merck in Rahway, New Jersey, upon an invitation from the company. Although the meeting resulted in TDR’s technical contributions to Merck’s studies of ivermectin, there was still no discussion about possible collaboration between Merck and TDR for development of ivermectin in human onchocerciasis. Similar exchanges of information between Merck researchers and TDR officials continued, but the opportunity for significant collaboration between TDR and Merck was not realized until 1982, when promising results became available from the Phase I study of ivermectin. The search for macrofilaricidal compounds continued to be the top priority for TDR, and the discovery of a new microfilaricide did not change the way TDR perceived the solution for the problem of onchocerciasis. A TDR official recalled in an interview that “Merck was not in touch with TDR for a couple of years, and TDR did not pursue it further.”15 In summary, TDR contributed to the discovery of ivermectin’s activity against microfilariae of O. volvulus in several ways. First, TDR recognized the lack of an effective tool to identify potential filaricides. Second, TDR recognized its potential role in taking an initiative to build a system for identifying filaricides, given weak economic incentives for pharmaceutical companies to invest in drug development for human filariasis. Third, TDR provided financial support to develop an animal model and screening system. Fourth, TDR facilitated the establishment of a screening system by mobilizing its international network of researchers and institutions. TDR’s unique position as an international body with a mandate to coordinate research work and provide funds in tropical diseases made these contributions possible. However, the discovery of ivermectin as a potential drug for human onchocerciasis occurred largely outside of TDR’s activities, and remained outside of TDR’s main focus until 1982, because TDR initially failed to appreciate the potential benefits of this drug for treating onchocerciasis. The major reason for TDR's lack of interest in ivermectin prior to Phase II trials was that ivermectin did not coincide with TDR’s priority target, macrofilaricides. Furthermore, TDR thought that microfilaricides would have severe side effects, often called the "Mazzotti reaction," which is caused by killed microfilariae, as observed with DEC.16 TDR’s contribution to the development of ivermectin at the discovery stage was critical, but indirect: TDR contributed by creating a receptive environment for finding an effective filaricide through its establishment of a screening system, but TDR’s priority was not yet focused on ivermectin. 2.2 Clinical trials Clinical trials of ivermectin began in 1981 with the Phase I trial in Senegal,17 and were followed by another trial in Paris.18 These trials were independently organized and 15 Interview No. 4 and 5 with a TDR official (June 26, and September 12, 1996). 16 Interview No. 4 with a TDR official (June 26, 1996). 17 Aziz, MA. Efficacy and tolerance of ivermectin in human onchocerciasis. The Lancet 2:171-3, 1982. 18 Coulard JP. Treatment of human onchocerciasis with ivermectin. Bull. Soc. Pathol. Exot. Filiales. 76:

681-8, 1983.

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paid for by Merck, based on its decision to go ahead with Phase I trials. Annex I lists the major Phase I~IV clinical trials with data on their publications and major sources of funding. The study in Senegal began with a very low ivermectin dose of 5 µg/kg for safety reasons, and found that a single dose of ivermectin, as low as 30 or 50 µg/kg, substantially decreased the number of skin microfilariae, and the effect was sustained for at least 6 months. No serious adverse reaction was observed. The second study in Paris with West African immigrants confirmed these results, and showed that doses up to 200 µg/kg were well tolerated. Dr. Mohamed Aziz of Merck was the driving force behind these initial clinical trials. The dialogue between Merck and TDR regarding ivermectin picked up in 1982, when Merck officials visited Geneva to present the results from the Phase I trials. The results from the Senegal study were about to be published in The Lancet.19 At that meeting, the two parties and OCP reviewed available data on the use of ivermectin in human onchocerciasis.20 Although still somewhat skeptical about the outcomes from the Phase I studies, which were conducted with lightly infected patients,21 TDR became interested in the potential of the drug, prompted by: good tolerability; sustained efficacy at low dose; and the absence of Mazzotti-like reactions.22 These results were unexpected, from TDR’s perspective, and provided the first strong evidence that ivermectin was a major breakthrough. One Merck participant at this meeting recalled that, in response to a question about price, Merck told TDR that its guiding principles in the development of this drug were: first, to follow the science; second, to follow the regulatory authorities; and then, to address the policy decisions on pricing and distribution.23 (Since we could find no written documents on this meeting in TDR records, we were not able to cross-check this point.) The decision was then made that Merck and TDR would proceed jointly to the next step, solving one problem at a time. Interviews and documents suggest that collaboration between these two major actors began with a mixture of mutual wariness about the other organization and a shared hope that they could establish scientific evidence of the efficacy of ivermectin against onchocerciasis. During the following stages of Phase II and Phase III trials, Merck continued to fund most of the clinical studies, with some financial contributions from OCP and TDR for selected studies. Therefore, financial contributions from TDR were not significant at this stage. TDR, however, made important contributions to the clinical trials in two other ways. First, TDR’s existing network facilitated Merck’s ability to develop collaborative relationships with onchocerciasis researchers and institutions to conduct a wide range of activities in nine African countries. Second, TDR made technical contributions to the

19 Aziz, MA. 1982 op. cit. 20 Interview No. 9 with a Merck official (August 19, 1996). 21 Skepticism about the effectiveness of ivermectin for onchocerciasis was also expressed from outside of

TDR, for example: Rougemont, A. Ivermectin for onchocerciasis. The Lancet, November 20, 1982. Also see the reaction from Aziz MA. et al. to Rougemont’s article: Ivermectin in onchocerciasis. The Lancet, December 25, 1982.

22 Report of the Steering Committee of the Scientific Working Group on Filariasis, July 1983 to June 1988. pp. 36-37.

23 Interview No. 9 with a Merck official (August 19, 1996).

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clinical trials by participating in the design of study protocols, and by supporting applied research on onchocerciasis treatment at the Onchocerciasis Chemotherapy Research Center in Tamale, Ghana. The Center had been supported by TDR since 1978, and had been serving as the TDR core facility for the clinical trials of potential drugs for onchocerciasis, and for related research. Of particular relevance for ivermectin clinical trials was a new method devised by Dr. K. Awadzi of the Center to quantify clinical reactions to microfilaricides using a scoring system of commonly observed reactions.24 The method was used in a number of ivermectin clinical trials, and made it possible to compare the degrees of systemic reactions for DEC and ivermectin using a common metric, and eventually helped prove the advantage of ivermectin as a safe microfilaricide. TDR’s involvement increased substantially when Phase IV community-based trials began in 1987 (Figure 1). Thirteen studies were conducted between 1987 and 1989, and over 120,000 individual doses of ivermectin were given. Of a total of 13 community trials, TDR funded five studies in Liberia, Cameroon, Malawi, Guatemala, and Nigeria, and spent $2.35 million in total. This means that about two-thirds of TDR’s total financial resources spent between 1977 and 1995 for the development of ivermectin was spent on community-based trials between 1987 and 1989. For these three years, TDR spent between 25~35% of its total annual budget for all filariasis programs (about $2 million) for ivermectin (about $600,000 a year). OCP funded eight other studies in Ghana, Mali, Togo and Benin, Ivory Coast, Guinea, Burkina Faso, and Senegal. This substantial financial commitment by TDR shows its strong concern about the implications of ivermectin for onchocerciasis control programs. Before the studies began, there were some disagreements between Merck, donors, TDR and OCP about the need for large-scale community trials at this stage of drug development. Merck considered that the data on clinical trials were sufficient to establish ivermectin’s safety and efficacy based on the standard requirements for new drug registration.25 In fact, the registration of ivermectin for human onchocerciasis was submitted to the French health authorities in 1987 based on the studies of the first 1,206 patients, and approval was expected later that year. Some donors to TDR were also reluctant to fund additional large-scale clinical trials at the end of Phase III studies. TDR, however, argued that all planned community-trials were necessary to investigate: adverse effects; ophthalmic pathology and effects of ivermectin on skin lesions; and effects on disease transmission. Furthermore, given different geographical variations and strain differences (e.g., forest vs. savanna onchocerciasis) in both Onchocerca and its vector, TDR argued that the effects of ivermectin needed to be studied in widely differing areas.26 OCP also emphasized the importance of testing patient acceptability and ivermectin’s effects on disease transmission. OCP felt that it should not be involved in ivermectin treatment unless studies could show that community-based treatment interrupted disease transmission.27 24 Awadzi K. The chemotherapy of onchocerciasis II: Quantification of the clinical reaction to

microfilaricides. Annals of Tropical Medicines and Parasitology. 74(2): 189-197, 1980. 25 Interview No. 13 with a Merck official (September 10, 1996). 26 Minutes of the meeting with TDR, OCP and USAID on June 26, 1987. (TDR file, WHO/Geneva). 27 ibid.

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Eventually, the funding for community-based trials was made available, and studies were monitored by a subcommittee with representatives from the Scientific Committee on Filariasis, the Scientific Committee for Onchocerciasis Chemotherapy, WHO, and OCP. The studies showed that ivermectin treatment was largely well accepted, and could be administered in mass treatment campaigns with minimum medical supervision.28 In addition, some studies showed that community-based treatment reduced disease transmission, although the evidence was considered to be insufficient.29 The differences in attitude towards community-based trials between Merck and TDR illustrate their contrasting views on the eventual use of ivermectin. On the one hand, Merck was essentially looking at ivermectin as a drug to be used for individual patient treatment for therapeutic purposes, as with most of Merck’s other drugs. On the other hand, TDR, together with OCP, saw the drug as a new tool that could potentially interrupt disease transmission and thus could contribute to reducing disease prevalence in endemic communities. TDR and OCP regarded community-based trials under field conditions as a necessary step towards mass-treatment programs beyond individual treatment in hospitals under professional supervision. By advocating the need for community-based studies, TDR made an important contribution in strengthening the value of ivermectin in the onchocerciasis control strategy. In summary, TDR made contributions at the stage of clinical trials of ivermectin in three areas, through its provision of: organizational infrastructure for the studies; technical expertise; and financial resources. First, TDR played a crucial role in building a partnership between Merck and the onchocerciasis research communities, in which the company did not have strong business or research connections. Second, TDR provided technical inputs to the clinical studies through: supporting the discovery of a new method to quantify drug effects; influencing the study design by Merck; and conducting studies that Merck was not otherwise interested in. Third, TDR made financial contributions. Although TDR’s financial contributions were presumably much smaller than those paid by Merck,30 they were focused in areas where the public health implications had direct relevance to the role of TDR. Organizational and technical contributions made by TDR were crucial for the successful completion of clinical trials of ivermectin. Merck would have found it much more difficult to develop ivermectin without TDR’s expertise and network in developing countries.

28 De Sole, G. et al. Adverse reactions after large-scale treatment of onchocerciasis with ivermectin:

combined result from eight community trials. Bulletin of the World Health Organization. 67(6):707-719, 1989; and Pacque, MC. et al., Community-based treatment of onchocerciasis with ivermectin: acceptability and early adverse reactions. Bulletin of the World Health Organization. 67(6):721-730, 1989.

29 Report of a Meeting of the TDR/OCP/OCT Subcommittee for Monitoring of Community Trials of Ivermectin, Ouagadougou, Burkina Faso, January 25-27, 1989. (TDR/OCP/OCT/IVERMECTIN/89.3).

30 Information regarding the costs of research and development in general are not made available by Merck; this includes the costs of research and development for ivermectin.

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2.3 Registration On October 21, 1987, ivermectin was approved in France for human onchocerciasis. The French government was chosen by Merck for the following two reasons. First, Merck wanted to submit its application to a well-established agency that could carefully scrutinize the data. Second, the company recognized the advantage of the French review, which would facilitate registration in francophone countries.31 Although ivermectin is now used in countries outside of West Africa, separate registration in other countries is not required, because Merck decided to donate the drug, instead of selling it as anticipated initially. The registration application was prepared by Merck without any involvement of TDR. TDR, however, was very concerned with the pre-clinical data contained in the application, especially the data regarding safety. TDR was concerned that ivermectin might be neurotoxic and that its safety would depend on the integrity of the blood-brain barrier.32 TDR requested that Merck share the data on safety, but Merck was reluctant to establish a precedent of providing information that was usually disclosed only to regulatory authorities.33 After some negotiations, Merck agreed to have WHO representatives examine the relevant confidential documents at its corporate premises. There are two future issues related to the registration of ivermectin. First, the patent for ivermectin will expire in 1997. Both TDR and Merck do not expect any significant changes in the current arrangements for the use of ivermectin in the onchocerciasis treatment program, since the drug is produced only for the purpose of donation (for human use). The second issue is related to new indications for ivermectin, other than onchocerciasis, especially lymphatic filariasis and strongyloidiasis, but also scabies and perhaps lice. Lymphatic filariasis is caused by the worms Wuchereria bancrofti and Brugia malayi that are transmitted by a mosquito vector. It is estimated that about 120 million people are infected in 76 countries worldwide, with about 45 million infected cases in India, and 40 million infected cases in sub-Saharan Africa.34 The effectiveness of ivermectin for lymphatic filariasis has been examined since 1988. Available data suggest that ivermectin is at least as effective as DEC (a commonly used drug for treatment of lymphatic filariasis) in reducing microfilaraemia, and can be more effective if used in combination with DEC or albendazole.35 Strongyloidiasis is caused by Strongyloides strecoralis, and is endemic in the tropics and the sub-tropics. It is also found in rural areas of certain temperature zones

31 Communication from Merck officials on Novermber 27, 1996. 32 Memorandum from Chief, WHO/PHA, dated September 3, 1987. 33 Interview No. 3 with an OCP official (June 26, 1996). 34 TDR. Lymphatic Filariasis Infection and Disease: Control Strategies - Report of a Consultative Meeting

in Penang, Malaysia. August 1994. pp.1-2. 35 Information provided by TDR.

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such as Eastern Europe and the southern part of the United States.36 Estimates of the worldwide prevalence of strongyloidiasis vary from 3 million to 30 million.37 Studies demonstrate that a single dose of ivermectin (200 µg/kg) was more effective with fewer side effects in treating strongyloidiasis than thiabendazole38 and albendazole.39 The disease is attracting renewed interest in recent years, in light of the increasing number of AIDS cases, since strongyloidiasis is lethal in immunosupressed patients.40 A study by Torres et al. demonstrated that ivermectin was promising in the treatment of strongyloidiasis in patients with AIDS.41 The epidemiological features of lymphatic filariasis and strongyloidiasis have important implications for future decisions about ivermectin. The populations who might need ivermectin for treatment of these two diseases would most likely be different from those who need the drug for onchocerciasis, in terms of population size and purchasing power. These factors have direct economic implications for Merck’s decision on how to make ivermectin available for new indications. In other words, if there is a “market” for ivermectin for these two indications, unlike in the case for onchocerciasis, then the company may well decide to sell the drug. Although Merck has not publicly discussed these issues yet, since clinical trials are still underway, TDR could be faced with a new situation for ivermectin, if ongoing studies show that ivermectin is significantly better than existing drugs for treating lymphatic filariasis and strongyloidiasis. So far, TDR has contributed little to the discussion about ivermectin’s registration. However, the situation could change in the near future, because of the patent expiration and the potential new indications for the drug. In this situation, TDR could play an important role to ensure that maximum benefits of ivermectin are guaranteed for people who need the drug. 2.4 Production According to Tavis, “Ivermectin is fermented in Pennsylvania and shipped to the United Kingdom or Puerto Rico for chemical treatment. Then ivermectin is shipped to Holland where it is made into tablets for human use, and packaged in France.”42 As far

36 Walden, J. Parasitic diseases: Other round worms. Trichuris, Hookworm, and Strongylides. Primary

Care. 18(1): 53-74, 1991. 37 Genta, RM. Global prevalence of strongyloidiasis: Critical review with epidmiologic insights into the

prevention of disseminated disease. Reviews of Infectious Diseases. 11(5): 755-767, 1989. 38 Gann, PH. et al. A randomized trial of single- and two-dose ivermectin versus thiabendazole for

treatment of strongyloidiasis. Journal of Infectious Diseases. 169(5): 1076-9, 1994. 39 Darty, A. et al. Treatment of Strongyloides stercoralis infection with ivermectin compared with

albendazole. Transactions of the Royal Society of Tropical Medicine and Hygiene. 88(3): 344-5, 1994. 40 For example, Gompels, MA et al. Disseminated strongyloidiasis in AIDS: uncommon but important.

AIDS. 5:329-332, 1991. 41 Torres, JR. Efficacy of ivermectin in the treatment of strongyloidiasis complicating AIDS. Clinical

Infectious Diseases. 17(5): 900-2, 1993. 42 Tavis, L. River Blindness: The Merck Decision to Develop and Donate MECTIZAN. University of Notre

Dame Press, 1996. p.258.

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as we could determine, TDR has not been involved in any issues related to the production of ivermectin. 2.5 Pricing The price for ivermectin was a critical concern for all parties involved in the development process. In fact, it was among the key questions that WHO representatives asked in their first meeting with Merck in November 1982; at that time, Merck was not prepared to provide an answer.43 The decision by Merck to donate ivermectin evolved over time, through discussions within Merck and within WHO, and through the interactions of these two organizations. Our review of documents and our interviews suggest that there were conflicting views on the pricing issue inside both WHO and Merck until just before the public announcement in October 1987. TDR’s major objective, in the discussions over price, was to ensure a wide availability of ivermectin to the people in endemic countries who had limited purchasing power. In order to achieve this goal, WHO presented the following three options to Merck at a meeting on September 11, 1984:44

“In the event that the anti-filarial activity of Ivermectin is confirmed, the Company will: (1) provide to WHO, at the lowest possible price based on direct costs of

production, sufficient supplies of the drug for the public health sector of developing countries where the filarial infections are present; or

(2) arrange the manufacture of the drug under such terms, or (3) assist WHO in arranging manufacture, including licensing arrangement

and supply of pertinent know-how.”45 Merck rejected the second and third options. Also, the first option was modified, at Merck’s request, so that Merck’s interest in the product would be better protected, as follows:

“the Company will provide to WHO at the lowest possible price consistent with the interest of the Company in ensuring that the overall benefits received by it from the development of Ivermectin as an anti-filarial drug provides a reasonable return on its investment in the said development.”46

The Merck side had multiple objectives in the pricing issue. According to one interview: first, the company hoped to make the drug available to the most people who 43 Interview No. 9 with a Merck official (August 19, 1996). 44 Note for the record of the meeting held on 11 September 1984. (TDR file, WHO/Geneva). 45 Draft Memorandum of Intent dated September 11, 1984 (TDR file, WHO/Geneva). WHO’s discussions

with Merck about pricing for ivermectin were coordinated by Mr. Warren Furth (Assistant Director-General of WHO) with participation from divisions of various programs, including TDR and OCP.

46 Memorandum from WHO Legal Council dated January 29, 1985. (TDR file, WHO/Geneva).

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needed it, because it was the most useful drug for onchocerciasis with its excellent efficacy and safety profile; second, the company hoped to get some returns on its investment, although it was clear that the economic return of ivermectin as a product would be marginal, if any; and third, the company wanted to protect its good public image by ensuring that ivermectin was handled responsibly.47 Although these three objectives turned out to be incompatible as the development process proceeded, Merck attempted to balance these objectives, as was reflected in Merck’s activities. Possible pricing options for Merck were four, either: (1) to sell the drug at some price; (2) to provide the drug for use in the public sector, and to receive financial compensation from third-party payers; (3) to donate the drug free of charge with no economic compensation; and (4) to abandon the plan for development altogether. The process of making the final decision was not a linear one in which these options were examined and deleted one by one. Instead, the decision emerged through ongoing discussions and negotiations by weighing one option against the others. In considering the first option, Merck used a benchmark price of US$3 per treatment in its registration materials submitted to the French authorities. The price level was calculated based on an economic analysis using available information about similar filarial drugs, advantages of ivermectin, and production costs, etc.48 At a meeting in September 1987, just before the French approval was given, Merck representatives mentioned a lower price of $1 per treatment, in a meeting at WHO (including TDR and OCP representatives). WHO commented that $1 per treatment was not a realistic option in developing countries, and OCP told Merck that the overall cost of the drug and delivery must not exceed $0.50.49 As Merck began to realize that selling ivermectin at any price was not likely to happen, without compromising its first objective to make the drug widely available to people who needed it, the second option became viewed as a compromise to accomplish its three objectives at the same time. The company then began to seek third-party payers, such as the U.S. government and multilateral development agencies, to purchase the drug from Merck and thereby pay for some of Merck’s costs, while providing the drug free of charge to end users in endemic countries. At a meeting on February 3, 1986, Merck informed Dr. A.O. Lucas, then Director of TDR, of its “high level decision to make special financial arrangements which would enable provision of the drug in endemic areas at a most favorable price.”50 Then, on June 20, 1986, Merck informed Dr. Lucas, through a telex, that it was making “appropriate arrangements, if necessary with other interested parties, to make needed quantities of the drug available to these (endemic countries) governments and patients at no cost.” The task of finding a willing third-party

47 Interview No. 12 with a Merck official (September 10, 1996). 48 Interview No. 10 with a Merck official (September 9, 1996). 49 Minutes of a joint meeting between representatives of WHO and Merck Sharp and Dohme (MSD) in

Geneva, September 14, 1987 (TDR file, WHO/Geneva). 50 Travel Report Summary by Dr. A.O. Lucas, March 5, 1986 (TDR file, WHO/Geneva).

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payer, however, turned out be much more difficult than originally expected by Merck executives.51 The third option, donating ivermectin without any economic compensation, also appeared problematic for both Merck and WHO. Some people were concerned that the donation of ivermectin would reduce incentives of other pharmaceutical companies to invest in tropical disease drug development. Some people were also apprehensive that the image of a free drug might raise suspicions among recipients of ivermectin about its quality and efficacy, and thereby damage its acceptability. Indeed, it is reported that some WHO officials suggested that Merck not donate the drug.52 But at the same time, it was probably a non-option for Merck to terminate the development process of ivermectin for onchocerciasis, once clinical trials showed its potential benefits to millions of people in preventing them from becoming blind. As a company, Merck is proud of its corporate commitment to the improved health of society, and would have found it ethically difficult to abandon ivermectin for human use. In addition, such a decision could have produced serious damage to its public image. After vigorous discussion and debate within the company, as well as with WHO, for more than three years, Merck made the final decision to donate ivermectin “for as long as it might be needed.” The Merck-WHO joint announcement of the donation coincided with the public announcement of the French approval on October 21, 1987, in Washington D.C., and Paris. There were three additional factors that helped Merck make the decision to donate the drug. First, Merck’s business performance as a whole was very good at the time of decision, and senior management felt that it could afford to donate the drug.53 Second, the fact that ivermectin was a huge success in the veterinary market made it easier for internal advocates of donation to make their case inside the company. Lastly, ivermectin donations are tax deductible under the U.S. tax code for corporate donations. The total amount of tax deductions claimed by Merck to date is unknown, since this information is proprietary. Between 1988 and 1996, about 60 million treatments have been enabled through the Mectizan Donation Program. One writer estimated the tax deduction per tablet, but did not provide a figure for the total deduction to date. 54 Although the expected tax benefits were not a decisive factor in the company’s donation decision in 1987, these benefits might have provided a supporting argument for donation proponents within Merck. Merck’s decision to provide an indefinite donation of ivermectin was an important accomplishment for TDR. Although TDR did not initially expect this outcome, and it was Merck that made the historic decision, TDR contributed to the decision in two critical ways: first, TDR maintained an ongoing and positive dialogue with the company; and second, TDR articulated a consistent position on the price issue, 51 Minutes of a joint meeting between representatives of WHO and Merck Sharp and Dohme (MSD) in

Geneva, September 14, 1987 (TDR file, WHO/Geneva). Also interview No. 9 with Merck official (August 19, 1996).

52 Tavis, L. River Blindness: The Merck Decision to Develop and Donate MECTIZAN. 1996. 53 Interviews No. 9 (August 19, 1996) and No. 13 (September 10, 1996) with Merck officials. 54 Tavis, L. River Blindness: The Merck Decision to Develop and Donate MECTIZAN. p.258. 1996.

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emphasizing the reality of onchocerciasis control programs that operate under extremely difficult economic conditions in endemic countries. 2.6 Distribution Even after Merck’s decision to donate ivermectin, two difficult problems needed to be addressed: to establish an effective distribution mechanism; and to decide who should be in charge of such a mechanism. At the time of the joint announcement in October 1987, another series of negotiations between WHO and Merck were ongoing for the delivery system. The negotiations and the positions taken by Merck and WHO are discussed in this section. Merck was concerned about two main issues in the distribution of ivermectin in endemic countries. First, it was concerned about adverse effects, particularly side effects that might be unreported because of the lack of an established monitoring system (as found in Merck’s main markets). Serious side effects caused by ivermectin treatment might even damage the drug’s credibility in the successful veterinary market. Second, Merck was concerned about the possibility of diversion of the drug to a black market, or even to the animal drug market. In order to prevent such problems, Merck needed an effective distribution system with an ability to evaluate distribution and control capabilities of interested parties, most of whom were presumed to be national governments. Also, such a system would need a capacity to monitor implementation of the delivery and the use of ivermectin according to the agreed conditions. Merck, as a private company, wanted to avoid any involvement in publicly expressing its judgment about an individual government’s capability. Merck initially turned to WHO to design and implement the ivermectin delivery system. The Letter of Agreement signed by TDR and Merck on July 10, 1985, contains the first public record of Merck’s desire for WHO, with national health authorities, to establish appropriate programs for the efficient distribution of the drug.55 Merck repeatedly urged WHO for its active leadership in building a delivery mechanism for the drug, without receiving a clear response.56 Documents suggest that WHO was contemplating the pros and cons of various options for WHO’s involvement in distribution. For WHO, issues arose from two concerns: its legal status as a multilateral organization, which would not allow its association with a committee jointly run by a private firm; and the degree of control that WHO could exert over the process in various options.57 At one end of the spectrum of

55 Letter from Mr. R.D. Fluss of Merck dated May 17, 1985 with the signature for agreement by Dr. A. O.

Lucas of TDR on July 10, 1985. 56 For example, a letter from Mr. Roy Vagelos, CEO/Merck, to Dr. Halfdan Mahler, Director-General of

WHO, dated September 26, 1986; and “Agreed Subsequent Steps” at the Merck/WHO meeting on January 21-22, 1987 (TDR file, WHO/Geneva).

57 WHO internal document (sometime in late 1986 - at least after October, but precise date unknown, TDR file, WHO/Geneva).

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options, WHO could remain as an “advisor” to a committee established by Merck, and to individual countries that wished to receive the drug. This form of participation would not have any conflict with provisions of the WHO Constitution. At the same time, WHO’s control over decisions would be limited in this format. For example, if Merck attempted unilaterally to dissolve the committee, WHO could not effectively prevent such a move. At the other end of the spectrum, WHO could establish a group of experts who would assess the capacity of governments that requested ivermectin to implement an onchocerciasis treatment program using ivermectin. This option would not involve any conflict with the WHO Constitution, while allowing WHO to exert a high degree of control over decisions. But WHO hesitated to choose this option, because a negative assessment could deprive some countries of access to ivermectin. On September 22, 1987, just before the announcement of the registration approval, WHO finally communicated to Merck its proposal on the ivermectin distribution mechanism: an informal format of tripartite consultation approach among WHO, Merck, and the individual requesting country, instead of setting up a formal committee.58 WHO saw this approach as more effective in guiding the requesting countries to fulfill the necessary requirements to distribute and use ivermectin properly. But this format did not accommodate Merck’s desire not to be directly involved in the decision process. Then, five days later, on September 27, 1987, Merck informed WHO of its intention to establish an expert committee to review and approve drug requests.59 The committee, named the Mectizan Expert Committee, is funded by Merck, and includes seven international experts in tropical medicine and public health. The secretariat of the Committee is located at the Task Force for Child Survival and Development within the Carter Center, Atlanta, USA. Representatives of Merck, WHO, and the Center for Disease Control and Prevention (CDC) are present at the Committee meeting as technical liaison members. The functions of the Mectizan Expert Committee were defined as:

(1) to develop guidelines and standards for community-based treatment programs; (2) to review applications to implement community-based treatment programs; (3) to advise and assist applicants in the implementation of treatment programs; (4) to monitor the progress of programs; and (5) to facilitate the coordination and consolidation of existing programs and

funding initiatives.60 The Mectizan Expert Committee was organized in February 1988, and became an effective means of private-public collaboration for the delivery of ivermectin, involving Merck, WHO, 32 national governments (out of 34 endemic countries in Africa, Middle East, and Latin America), and 12 international Non-Governmental Organizations 58 Letter from Mr. W. Furth, ADG of WHO to Mr. J. Lyons, Executive Vice President of Merck dated

September 22, 1987. (TDR file, WHO/Geneva). 59 Telegram from Mr. J.T. Jackson, Senior Vise President for Human Health Marketing of Merck to Mr. W.

Furth, ADG of WHO dated September 27, 1987. (TDR file, WHO/Geneva). 60 Merck, The MECTIZAN Donation Program. May 31, 1996.

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(NGOs). Between October 1988 and May 1996, about 60 million ivermectin tablets were distributed to approximately 13 million people.61 (Additional information is provided in the next section on program implementation.) The Mectizan Expert Committee developed review criteria to ensure that “institutions have the capacity to deliver ivermectin effectively and in a medically-responsible manner.”62 According to the criteria, the applying parties (including national or local governments, hospitals, NGOs, and industrial or employee health care groups) should be able to: (1) determine target communities and persons for treatment; (2) define a treatment strategy; (3) develop and maintain an accurate record-keeping system; (4) identify and give medical care for cases with serious adverse effects; (5) assure the intended use of the drug; and (6) maintain regular, periodic cycles of treatment for at least 3 years. Once the Committee approves an application, it recommends to Merck that ivermectin be shipped to the applicant. (Costs for shipment and customs are paid by Merck.) Under this system, Merck successfully separated its logistical operations from the review and approval process. So far, the Committee has never turned down any application. Instead, it has worked with the requesting parties so that they can meet the requirements for approval. 2.7 Program Implementation Since September 1988, ivermectin has been delivered to end users through two channels under the Mectizan Donation Program. The majority of the supply is provided to requesting parties (mainly national governments and international NGOs) for community-based programs with an approval given to each request by the Mectizan Expert Committee. The second channel deals with a much smaller quantity (less than 1% in 1996), which is provided to individual hospitals and doctors through the Humanitarian Program operated directly by Merck from Paris. Table 1 shows a rapid growth of the donation program since its establishment in 1988. During eight years (1988-95), treatment programs began in 32 out of 34 onchocerciasis endemic countries (Annex II). In 75% of 32 countries with programs, some or all of the programs have continued for five years or more. In one-third of 32 countries, programs continued for eight years.63 Thirty-five percent of the total of 74 applications were sponsored by ministries of health, 55% by NGOs, and the remaining 10% by either the OCP or academic institutions. This successful expansion of the ivermectin treatment program was brought about by several major actors, including: Merck; the Mectizan Expert Committee and its secretariat; NGOs; national and local governments of endemic countries; and OCP. For example, OCP made an immediate launch of ivermectin treatment programs possible 61 ibid. 62 Mectizan Expert Committee. The Mectizan Donation Program: Community-Based Mass Treatment of

Onchocerciasis - Program Information. December 1994. 63 Mectizan Donation Program. MECTIZAN PROGRAM NOTES Issue 14, Fourth Quarter 1995.

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within OCP countries by providing national governments and NGOs with technical and logistic support. The active participation of NGOs in the ivermectin distribution program has been particularly important for the program. In 1992, they formed the Non-Governmental Development Organizations (NGDOs) Coordination Group for Ivermectin Distribution to improve coordination among themselves. A coordinator post was created with funding from NGOs, and is housed in the Prevention of Blindness Programme of WHO (PBL) in Geneva. The NGDOs Coordination Group meets twice a year, and discusses issues related to its objectives as listed below:

(1) to assist ministries of health in promoting and preparing national plans for the control of onchocerciasis by means of ivermectin;

(2) to provide practical guidelines for district program managers; (3) to provide information to other NGDOs and agencies that might consider

initiating ivermectin distribution programs.64 Building upon the achievements made by the collaborative partnership among various actors in the onchocerciasis treatment program with ivermectin, a new regional program for non-OCP African countries, the African Programme for Onchocerciasis Control (APOC), was launched in 1995. APOC is based on a partnership between governments and infected communities of participating countries, NGDOs, donors, and four co-sponsoring multilateral agencies (i.e., FAO, UNDP, WHO and the World Bank). The APOC’s goal is to eliminate onchocerciasis as a disease of public health and socio-economic importance in the non-OCP countries in Africa, where more than 85% of people (about 15 million) who are currently affected by the disease live, by establishing sustainable community-based ivermectin treatment programs over a period of 12 years.65 TDR has been playing an important role in building the technical basis for APOC through its Task Force on Onchocerciasis Operational Research, which was created in 1993. APOC requested the Task Force to accelerate its activities to resolve a number of issues that were critical in designing the APOC’s strategies.66 These issues include:

a) the location of high risk communities that require ivermectin treatment; b) the effect of ivermectin treatment on onchocerciasis skin disease; c) indicators for treatment on areas where skin disease is the main complication

of the disease; d) sustainable approaches to community self-treatment; e) simple methods for monitoring control; and

64 NGDO Group for Ivermectin Distribution. Procedural Manual for Ivermectin Distribution Programmes.

1993. 65 The APOC Committee of Sponsoring Agencies (CSA). African Programme for Onchocerciasis Control

- Programme Document. December 1996. CSA is composed of co-sponsors of the Programme, namely: FAO, UNDP, WHO, and the World Bank.

66 Remme. J.H.F. The African Programme for Onchocerciasis Control: preparing to launch. Parasitology Today. 11:403-406. 1995.

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f) the feasibility of focal vector eradication.67 Some of the early findings of research activities conducted by the Task Force have already made critical contributions to APOC. For example, a multi-country study conducted in Ghana, Nigeria, Cameroon, Uganda, and Tanzania demonstrated that onchocerciasis skin disease is a serious public health problem with a burden of severe itching and social stigma associated with skin legions imposed on affected individuals and communities.68 Another multi-country study on the community self-treatment approach demonstrated that communities were able to design and successfully carry out own ivermectin delivery systems by themselves after they were given necessary health education. This community directed treatment approach is now adopted by all APOC countries as the treatment implementation strategy at community level.69 As the ivermectin development process concluded, the drug became an integral part of onchocerciasis control programs. While TDR does not have a direct mandate in program implementation, TDR has been continuously involved in the ivermectin treatment for onchocerciasis through the operational research. Under the APOC, a new mechanism for international cooperation for the ivermectin treatment, outcomes of these research activities by TDR have been making direct contributions to the improvements in the implementation of ivermectin treatment programs.

3. CONCLUSIONS The discovery, development and distribution of ivermectin have dramatically changed available onchocerciasis control strategies from the previously limited choice between vector control by expensive spraying activities and chemotherapy with agents that cause dangerous side effects, to the current option of successful mass-treatment with minimal safety problems. Emerging evidence suggests that annual community treatment by ivermectin has reduced the prevalence of infection. In Cameroon, after 6 years of consecutive ivermectin treatment in a community, the prevalence of skin microfilariae and the mean microfilarial skin densities were reduced by 55% and 77% among children who did not receive the treatment.70 A study in Sierra Leone demonstrated that the mean number of larvae per infected blackfly fell from 8.7 to 5.8 (21% decrease) during the four-year ivermectin community treatment.71 It is still uncertain whether annual treatment with ivermectin will reduce the incidence of infection or will interrupt disease

67 TDR. Worklplan of the Task Force on Onchocerciasis Operational Research. January 12, 1996. 68 The Pan-African Study Group on Onchocerciasis Skin Disease. The Importance of Onchocerciasis Skin

Disease - Report of a multi-country study. TDR Applied Field Research Reports No.1. 1995. (TDR/AFR/RP/95.1)

69 TDR. Community Directed Treatment with Ivermectin - Report of a multi-country study. TDR Applied Field Research Reports. 1996. (TDR/AFR/RP/96.1).

70 Boussinesq, M. et al. Effect of repeated treatment with ivermectin on the incidence of onchocerciasis in Northern Cameroon. American Journal of Tropical Medicine and Hygiene. 53(1); 63-67, 1995.

71 Chavasse, DC. et al. Low level ivermectin coverage and the transmission of onchocerciasis. Transactions of the Royal Society of Tropical Medicine and Hygiene. 89: 534-537, 1995.

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transmission. Nevertheless, the ivermectin treatment story is a major success in terms of the greatly reduced disease burden associated with onchocerciasis. These positive results have contributed to growing enthusiasm about ivermectin in the international community. In November 1990, six African nations (Cameroon, Central African Republic, Chad, Congo, Equatorial Guinea, and Gabon) passed a resolution calling for the acceleration of onchocerciasis treatment programs. In September 1991, the Pan American Health Organization and the WHO approved a resolution to eliminate onchocerciasis as a public health program in the Americas by 2002. In 1995, the World Bank launched the African Program for Onchocerciasis Control (APOC).72 The success of ivermectin depended on three unusual events that were hard to predict at the outset: an evolving and complex collaboration between TDR and a private multinational pharmaceutical company; Merck’s decision to donate the drug for an indefinite period of time and amount; and the establishment of an innovative delivery system through the Mectizan Expert Committee. This report reviewed TDR’s activities throughout the ivermectin development process. Table 2 summarizes the results of our analysis on the relative involvement of seven actors at each stage of the product development process for ivermectin. As shown in this report, TDR made significant contributions at the stages of clinical trials, decisions on pricing, and program implementation. TDR also made moderate contributions to the discovery of ivermectin and to discussions on distribution. TDR’s contributions were negligible in the processes of registration and production. This pattern fits with TDR’s mandate in promoting basic research and clinical trials, indicating that TDR’s performance in ivermectin development was appropriately guided by its mandate. Our analysis also identified three important cross-cutting themes in TDR’s contributions to the development of ivermectin: First, TDR demonstrated a capacity to shift its priorities with the accumulation of scientific evidence, as shown by the changing focus of its filariasis policy from a search for a macrofilaricide to acceptance of a microfilaricide. TDR was persuaded by scientific data, despite its organizational investment in the search for a macrofilaricide and its skepticism about the safety and efficacy of a microfilaricide. This flexibility reflects the evidence-based nature of decisions that shaped TDR strategies. Second, TDR demonstrated a willingness to participate in innovative forms of public-private collaboration for tropical disease drug development. Our analysis suggests that the two main actors, Merck and TDR, felt uneasy with each other, especially at the beginning of their relationship. They presented strikingly different organizational cultures and objectives, which sometimes created distrust and tension in their relationship. At the same time, however, they also came to understand that each side needed the other to accomplish the common goal: to make ivermectin available to the

72 TDR. Report of the Meeting on Prospects for Elimination of Some TDR Diseases. September 21, 1995.

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people who needed the drug in order to prevent blindness and skin disease with severe itchiness. Gradually, mutual confidence was built between individuals in the two organizations. And in that sense, TDR helped develop a common goal of making an extraordinary drug available to poor people in poor countries, and thereby producing significant health benefits. The decisions on pricing and on distribution were particularly important achievements of this evolving collaboration and common goal. Third, TDR maintained its commitment to public health goals in its involvement with the development of ivermectin. This approach was reflected in TDR’s insistence on the need for community-based trials, despite some skepticism that existed outside of TDR. TDR’s vision that ivermectin could be used on a mass scale, beyond the therapeutic treatment of infected individuals, led to the community-based trials, and eventually established convincing evidence for the present role of ivermectin in the mass-treatment strategy for onchocerciasis control. This review of TDR’s involvement in the process of ivermectin development reveals the complexity of issues associated with drug development for tropical diseases. The process from the discovery of ivermectin’s activity against microfiraliae of O. volvulus in 1978 to the successful distribution program in the 1990s was not an easy or direct path. The process was filled with conflicting views, ambiguity, frustration, and unexpected turns. This report shows that ivermectin’s success depended on a number of organizational, individual, and pharmacological factors, and suggests that the experience may be difficult to replicate for other tropical disease treatments.73 However, the case of ivermectin development also shows that an innovative approach to private-public collaboration can transform perceived conflicts of interest into opportunities for achieving common goals. In this regard, we find that TDR’s policymaking mechanism, with its emphasis on scientific evidence and public health goals, enabled the organization to respond creatively to emerging situations and opportunities. Overall, this review of ivermectin development illustrates the importance of TDR’s role as an international body that articulates and represents the needs of people who are exposed to threats of tropical diseases.

73 Reich, MR et al. International Strategies for Tropical Disease Treatments: Experiences with

Praziquantel. Boston, MA: Harvard School of Public Health. 1995.

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Annex I Major Publications of Clinical Trials and Operational Research of Ivermectin for Human Onchocerciasis

Principal Investigators

Title Protocol Country Publication(Period)

Majorsource of funding

TDR Project ID & funding

Phase I Aziz, MA (1) Efficacy and tolerance of ivermectin in

human onchocerciasis (2) Ivermectin in onchocerciasis

32 onchocerciasis patients given single dose of 5-50 µg/kg

Senegal (1981)

(1) Lancet 1982; 2: 171-3 (2) Lancet 1982; 2: 1456-7

Merck

Coulard, JP (1) Treatment of human onchocerciasis with ivermectin (2) Ivermectin in onchocerciasis

12 onchocerciasis patients given single dose of 150-200µg/kg

France (1) Bull. Soc. Pathol. Exot. Filiales 1983; 76: 681-8 (2) Lancet 1984; 2: 526-7

Merck

Open-dose finding Awadzi, K. (1) Ivermectin in onchocerciasis (letter)

(2) The chemotherapy of onchocerciasis X. An assessment if four single regimens of MK-933 (ivermectin) in human onchocerciasis

single dose of 50, 100, 150, 200 µg/kg

Ghana (1) Lancet 1984; 2: 921 (2) Ann. Trop. Med. Parasitol. 1985; 79: 63-78

Merck, OCP, TDR

ID 780510 $ ??

Phase II (1) Greene, BM., Taylor, HR et al. (2) Taylor HR. et al.

(1) Comparison of ivermectin and diethylcarbamazine in the treatment of onchocerciasis (2) Comparison of the treatment of ocular onchocerciasis with ivermectin and diethylcarbamazine

single dose of IVM 200 µg/kg vs. DEC 50, 100mg x 8days vs. placebo

Liberia (1)N. Engl. J. Med. 1985; 313: 133-8 (2) Arch. Ophthlmol. 1986; 104: 863-70

OCP, Merck, NIH, Rockefeller Foundation

Lariviere, M., Aziz Double-blind study of ivermectin and diethylcarbamazine in African onchocerciasis patients with ocular involvement

Mali Lancet 1984; 2: 174-7 Merck

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Principal

Investigators Title Protocol Country Publication

(Period) Major

source of funding


Diallo, S., Aziz, Lariviere, Diallo, Diop-Mar, N’Dir, Badiane, Py, Schulzt-Key, Gaxotte et al.

A double-blind comparison of the efficacy and safety of ivermectin and diethylcarbamazine in a placebo controlled study of Senegalese patients with onchocerciasis

IVM: single dose 12mg (200 µg/kg) vs. DEC: 50mgx2days, & 100mgx2x6days vs. placebo

Senegal Trans. R. Soc. Trop. Med. Hyg. 1986; 80: 927-34

Merck

Schulzt-Key et al. (1) Treatment of human onchocerciasis: The effects of ivermectin on the parasite (2) Efficacy of ivermectin on the reproductivity of female O. volvulus

(1) Tropical Med. Parasite, 1985; 36: 20 (2) Trop. Med. Parasitol. 1986; 37: 89

TDR, Merck OCP, Merck

(1) Awadzi, K, Dadzie, Schulzt-Key, Gilles, Fulford, Aziz (2) Dadzie, KY, Bird, Schulzt-Key, Gilles, Aziz, Awadzi

(1) The chemotherapy of onchocerciasis XI. A double-blind comparative study of ivermectin, diethylcarbamazine, and placebo in human onchocerciasis in Northern Ghana (2) Ocular findings in a double-blind study of ivermecin vs. DEC vs. placebo in the treatment of onchocerciasis

IVM: single dose 12mg vs. DEC:1300mgx8days vs. placebo

Ghana (1) Ann. trop. Med. Parasitol. 1986; 80: 433-42 (2) Br. J. Ophthalmol. 71(2): 78-85, 1987 Feb.

OCP, Merck, TDR

25

Principal


(Period) Major

source of funding


Phase III (1) White, AT, Newland, Taylor, Aziz, Greene (2) Newland. HS, Greene, BM.,

(1) Controlled trial and dose finding study of ivermectin for treatment of onchocerciasis (2) The effect of single dose ivermecin therapy on human O. volvulus infection with onchocercal ocular involvement

100, 150, 200 µg/kg, or placebo

Liberia (1) J. Infect. Dis. 1987; 156(3): 463-70 (2) Br. J. Ophthamol. 1988 Aug.; 72: 561-9

Merck

Soboslay, PT. et al. (Taylor)

Ivermectin effect on microfilariae of O. volvulus after a single oral dose in humans

sibgle dose of 100, 150, and 200 µg/kg vs. placebo

Liberia Trop. Med. Parasitol. 1987; 38: 8-10

OCP, NIH, Merck, Rockefeller

Albeiz EJ. et al ( Greene, Taylor)

Chemotherapy of onchocerciasis with high doses of DEC or a single dose of ivermectin: microfilaria levels and side effects

DEC: normal dose + 30mg/ kg/d over 1 wk, Ivermectin: single dose of 150mg/kg, vs. placebo

Liberia Trop Med Parasitol. 39(1): 19-24, 1988 Mar.

OCP

Cupp, EW., Taylor, Aziz, Greene

The effects of ivermecin on transmission of O. volvulus.

Liberia Science 1986; 231: 740-2 non TDR

Taylor HR, Samba RD, White, Greene,

Ivermectin treatment for patients with severe ocular onchocerciasis

39 patients treated with annual dose of 100, 150, or 200 µg/kg of ivermectin, or placebo for three years

Liberia Am. J. Trop. Med. Hyg. 1989; 40: 494-500

OCP, Merck, NIH

Pacque M. Munos, Greene, Taylor

A comparison of 6-, 12-, and 24-monthly dosing with ivermecin for treatment of onchocerciasis

Liberia J. Infect Dis. 163(2): 376-80, 1991

Vingtain, P., Pichard, Ranque, P.

[Ivermecin and human onchocerciasis. A study of 234 onchocerciasis patients in the Republic of Mali] (French)

100, 150, 200 µg/kg vs. placebo,

Mali Bull. Soc. Pathol. Exot. Filiales 1988; 81: 260-70

Merck, OCP

Ranque. P., Aziz, M., Pichard, E.

A double-blind study of ivermectin and placebo in onchocerciasis in Mali

Mali Proceedings of the IXth Int’l Congress of Infectious and Parasitic Diseases 1986; Munich: 140

Merck

26

Principal


(Period) Major

source of funding


Albiez, EJ. et al. Histological examination of onchocercomata after therapy with ivermecin

single dose 100, 150 or 200µg/kg ivermectin

Mali & Liberia

Trop. Med. Parasitol. 1988; 29: 93-9

OCP

Hussein, S., Bird, A., Jones, B.R.

Ocular lesions seen in phase III trial of ivermecin therapy of onchocerciasis in Togo

100, 150, 200 µg/kg vs. placebo

Togo Trop. Med. Parasitol. 1987; 38: 67

Merck, OCP

Mossinger. J. et al. (Schulz-Key)

Emergence of O. volvulus microfilariae from skin biopsies of patients treated with ivermectin

skin snip sample from Phase III study in Togo with single dose of 100, 150, and 200 µg/kg ivermectin

Togo and Germany

Trop. Med. Parasitol. 1987; 38: 69

Merck, EC, German Agency for Technical Coopera-tion

Lariviere, PM., Aziz, M. et al

[A study in the Ivory Coast (1985-87) of the efficacy and tolerance of ivermectin (Mectizan) in human onchocerciasis: I A comparative double-blind study of 220 patients with onchocerciasis treated with a single dose of 100, 150, 200 µg/kg] (French)

single dose of 100, 150, 200 µg/kg

Ivory Coast (1985-87)

Bull. Soc. Pathol. Exot. Filiales 1989 Jan; 82 (1): 35-47

Merck

Lariviere, PM. Aziz, M. et al.

[A study in the Ivory Coast (1985-87) of the efficacy and tolerance of ivermectin (Mectizan) in human onchocerciasis: II. Evaluation in the light of mass campaign in the effects of yearly or half-yearly administration of a single dose of 100, 150, 200 µg/kg] (French)

yearly or half-yearly dose of 100, 150, 200 µg/kg



Merck

Lariviere, PM. Aziz, M. et al.

[A study in the Ivory Coast (1985-87) of the efficacy and tolerance of ivermectin (Mectizan) in human onchocerciasis: III. The tolerance and efficacy of a single dose of 100, 150, 200 µg/kg] (French)

single dose 150 µg/kg given to children



Merck

Prod’hon, J. [Ivermecin and reduction of the rate of simuliids in a human onchocerciasis focus](French)

Ivory Coast Ann. Parasitol. Hum. Comp. 1987; 62: 590-8

non TDR

Vingtain, P., Longitudinal study of microfilarial infestation and humoral immune response to filarial and retinal antigens in onchocerciasis

Ophthalmic Res. 1988; 20: 95

27

patients treated with ivermectin Principal


(Period) Major

source of funding


Community-based trials (1) Pacque MC. Greene, Taylor et al. (2) Trpis M, Taylor HR. et al. (3) Pacque, Munoz, Greene, Taylor (4)Taylor, Pacque, Munoz, Greene (5) Pacque, Munoz, Greene, White, Dukuly, Taylor (6) Pacque, Munoz, Poetscke, Foose, Greene, Taylor

(1) Community-based treatment of onchocerciasis with ivermectin: acceptability and early adverse reactions (2)Effect of mass treatment of a human population with ivermectin on transmission of O. volvulus by Simulium yahenese (black fly) in Liberia, West Africa (3)Community-based treatment of onchocerciasis with ivermectin: safety, efficacy, and acceptability of yearly treatment (4) Impact of mass treatment of onchocerciasis with ivermecin on the transmission of infection (5) Safety of and compliance with community-based ivermectin therapy (6) Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution

(1) (2) annual dose of 150 µg/kg ivermectin to 14,000 people (3) annual treatment for 3 yrs. (4) annual treatment for 3 yrs.

Liberia (1987-88)

(1) Bull WHO 67 (6):721-30, 1989 (2)Am. J. Trop. Med. Hyg. 1990 Feb; 42(2): 148-56 (3) J. Infec. Dis 163(2): 381-5, 1991 Feb. (4) Science 250(4977): 116-8, 1990 Oct. 5 (5) Lancet. 335(8702): 1377-80. 1990 Jun 9 (6) Lancet. 336(8729): 1486-9. 1990 Dec 15

(1) TDR (2)USAID, and TDR

ID 870096 $625,351

28

Principal


(Period) Major

source of funding


(1) Moyou Somo R. et al. (2) Chippaux J-P. et al.

(1) A community-based trial of ivermectin for onchocerciasis control in the forest of southwestern Cameroon: Clinical and parasitologic findings after three treatment (2)Absence of any adverse effect of inadvertent ivermectin treatment during pregnancy

(1) once or twice a year treatment: (body weight) 15-29kg, 3mg 30-44kg, 6mg 45-64kg, 9mg >65kg, 12mg (2)

Cameroon - southwest (1988-91) Cameroon- North (1990-91)

(1) Am J Trop Med Hyg. 1993 Jan.; 48(1): 9-13 (2) Trans. Royal Soc. Trop. Med. Hygiene. 87(3): 318, 1993 May-Jun

TDR, and Cameroon Institute of Medical Research and Studies of Medical Plants

ID 870319 $ ?? ID 870336 $707,800

Burnham GM. Adverse reactions to ivermectin treatment for onchocerciasis: Results of a placebo-controlled, double-blind trial in Malawi

annual dose of 150-200 µg/kg for 3 years

Malawi (1989-91)

Trans R. Soc Trop Med Hyg. 87(3):313-7, 1993. May-Jun

TDR ID 870069$95,979

Collins RC, et al. (Cupp).

(1) Ivermectin: reduction in prevalence and infection intensity of O. volvulus following biannual treatments in five Guatemalan communities (2)The effects of repetitive community-wide ivermectin treatment on transmission of O. volvulus in Guatemala

biannual treatment with ivermectin or placebo for 3 years

Guatemala (1988-90)

Am J Trop Hyg 1992 Aug; 47(2): (1) 156-69 (2) 170-80

TDR ID 870340$450,301

Abiose Nigeria TDR ID 870122$9,885 ID 870456 $447,916 ID 890134 $65,116

Doumbo, Soula, Kodio, Perrenoud

[Ivermectin and pregnancy in mass treatment in Mali] (French)

Mali(Tienfala)

Bull Soc Pathol Exot. 85(3): 247-51, 1992

OCP

29

Principal


(Period) Major

source of funding


(1) Dadzie KY. et al. (2) Awadzi K. Dadzie, Klager, Gilles

(1) The chemotherapy of onchocerciasis. XIII. Studies with ivermectin in onchocerciasis patients in northern Ghana, a region with long lasting vector control (2) Ophthalmological results from a placebo controlled comparative 3-dose ivermectin study in the treatment of onchocerciasis

single dose of 100, 150, 200 µg/kg of ivermectin vs. placebo

Ghana (Bui)

(1) Trop Med Parasitol. 40(3): 361-6, 1989 Sep (2) Trop Med Parasitolo. 40(3): 355-60, 1989 Sep. .

OCP & Merck

(1) Remme J. et al (2) De Sole G. et al. (3) Dadzi KY et al. (4)Dadzie KY. et al. (5)Alley ES. et al .

(1) A community trials of ivermectin in the onchocerciasis focus of Asubunde, Ghana I: Effect on the microfilarial reservoir and the transmission of O. volvulus (2) A community trials of ivermectin in the onchocerciasis focus of Asubunde, Ghana II: Adverse reactions (3) (4)Changes in ocular onchocerciasis after two rounds of community-based ivermectin treatment in a holo-endemic onchocerciasis focus (4)The impact of five years of annual ivermectin treatment on skin microfilarial loads in the onchocerciasis focus of Asubende, Ghana

(1) (2) 2 years (3) (4) 16 and 24 months after annual treatment with 150 µg/kg ivermectin (5) 5th year observations

Ghana - Asubende (1987-91)

(1) Trop Med Parasitol. 40(3): 367-74, 1989 Sep (2) Trop Med Parasitol.. 40(3):375-82, 1989 Sep (3) Roayal Soc. Trop. Med. Hyg. 84: 103-108, 1990 (4)Trans R Soc Trop Med Hyg. 85(2): 267-71, 1991 Mar-Apr. (5) Trans R Soc Trop Med Hyg. 88(5):581-4, 1994 Sep-Oct

OCP

30

Principal


(Period) Major

source of funding


De Sole, G. et.al. Adverse reactions after large-scale treatment of onchocerciasis with ivermectin: combined results from eight community trials

Togo, IvoryCoast

Bull WHO. 67(6): 707-719, 1989

Guinea, Burkina Faso, Senegal (1987-88)

OCP

(1) Whitworth JAG et al. (2)Whitworth, JA. et al. (Taylor) (3)Whitworth JAG, et al. (Taylor) (4) Whitworth JAG. et al. (Taylor) (5) Whitworth JAG. et al. (Taylor) (6) Chavasse DC, Post, Lemoh, Whitworth

(1) Community-based treatment with ivermectin (2)A community trial of ivermectin for onchocerciasis in Sierra Leone: clinical and parasitological responses to initial dose (3) A community trial of ivermectin for onchocerciasis in Sierra Leone: adverse reactions after first five treatment rounds (4)Effects of repeated doses of ivermectin on ocular onchocerciasis: community-based trial in Sierra Leone (5) A community trial of ivermectin for onchocerciasis in Sierra Leone: clinical and parasitological responses to four doses given at six-monthly intervals (6) The effect of repeated doses of ivermectin on adult female Onchocerca volvulus in Sierra Leone

(1) single dose 100-200 µg/kg ivermectin vs. placebo given to 1252 people (2) & (3) double-blind trial with single dose of 150 µg/kg ivermectin and placebo given to 1745 people (4) double-blind, placebo-controlled (5)after 4 treatments with 6-monthly 150 µg/kg ivermectin and placebo (6) after 5 treatments with 150 µg/kg ivermectin with 6 month intervals

Sierra Leone

(1) Lancet, July 9, 1988: 97-98 (2) Trans R Soc Trop Med Hyg. 85(1): 92-6, 1991 Jan-Feb. (3) Trans R Soc Trop Med Hyg. 85(4):501-5, 1991, Jul-Aug (4) Lancet. 338(8775): 1100-3, 1991 Nov.2 (5)Trans R. Soc Trop Med Hyg. 86(3): 277-80, 1992 May-Jun (6) Trop Med Parasitol. 43(4): 256-62, 1992 Dec.

31

Principal


(Period) Major

source of funding


Operational research∗ Richards F, Flores RZ et al.

Community participation in the Guatemalan national ivermectin distribution program (1) KAP of onchocerciasis: a survey among residents in an endemic area in Guatemala targeted for mass chemotherapy with ivermectin

Guatemala (1) Soc Sci Med. 32 (11): 127 5-81, 1991

ID 900589$51,150

Ojodu (1) Preliminary observation on the distribution of ivermectin in Nigeria for control of river blindness: (2) Comparison of three strategies for mass distribution of ivermectin in Achi, Nigeria

Nigeria (1) Ann Trop Med Parasitol. 86(6): 649-55, 1992 Dec. (2): Ann Trop Med Parasitol 87(4): 399-402; 1993 Aug.

ID 910393 $100,000 ID 920348 $200,000

Abiose Ranking questionnaire approach for rapid selection of communities in need of ivermectin for onchocerciasis control

Nigeria ID 910455$18,930

Yumkella Women, onchocerciasis and ivermecin in Sierra Leone

SierraLeone

ID 920333$37,472

Coulibaly Cost effective study of onchocerciasis control strategy with ivermecin

Mali ID 920772$50,500

∗ The list of TDR operation research projects in this page is incomplete, because we were not able to obtain full information from TDR.

32

Annex II Onchocerciasis-Endemic Countries and Ivermectin Treatment Programs Ivermectin treatment programs exist in the following 32 countries out of 34 onchocerciasis-endemic countries, except Angola and Colombia where treatment programs do not exist or are currently inactive(*) : Africa

• Angola(*) • Benin • Burkina Faso • Burundi • Cameroon • Central African Republic • Chad • Congo • Equatorial Guinea • Ethiopia • Gabon • Ghana • Guinea • Guinea Bissau • Ivory Coast • Liberia • Malawi • Mali • Niger

• Nigeria • Senegal • Sudan • Sierra Leone • Tanzania • Togo • Uganda • Zaire

Latin America

• Brazil • Colombia(*) • Ecuador • Guatemala • Mexico • Venezuela

Middle East

• Yemen

Source: Merck & Co., Inc.

33

Annex III Non-Governmental Organizations Involved in Ivermectin Treatment Programs

• Africare • Christoffel-Blindenmission (CBM) - Behsheim, Germany • Helen Keller International • International Eye Foundation • Interchurch Medical Assistance • International Federation for Education & Self-Help • Lion’s Clubs International Sight First Program • Organisation pour la Prevention de la Cecite (OPC) - Paris, France • Pan American Health and Education Foundation (PAHEF) • River Blindness Foundation (Since 1 May 1996, the organization merged into the

“Global 2000 River Blindness Program of the Carter Center Inc.”) • Sight Savers - West Sussex, United Kingdom • Task Force for Child Survival • U.S. Committee for UNICEF • World Vision

Source: Merck & Co., Inc.

34

Figure 1. Allocation of Annual TDR Filariasis Budget to Antifilarial Drug Screening System, and to Development of Ivermectin for Onchocerciasis and Lymphatic Filariasis

(1975-1996)

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

3,000,000

3,500,000

75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96

Year

Dol

lars

Filariasis budget alloctaed to other purposesFilariasis budget allocated to ivermectin for lymphatic f ilariasisFilariasis budget allocated to ivermectin for onchocerciasisFilariasis budget allocated to screening system

35

Table 1. Number of Ivermectin Treatments by Year of Application Approval (September 1988-1995)

TYPE OF APPLICATION INITIAL PROGRAM CONTINUATION

PROGRAM TOTAL

TREATMENTS Number of Treatments Number of Treatments

Year Applications Proposed Applications Proposed 1988 1

255,000 0 - 255,000

1989 16 239,220

0 - 239,220

1990 16 708,255

3613,247

1,321,502

1991 14 777,194

172,002,617

2,779,811

1992 9 702,305

84,177,196

4,879,501

1993 8 2,101,456

256,948,814

9,050,270

1994 1 310,304

2711,491,505

11,801,809

1995 9 1,423,886

2214,183,818

15,607,704

Total 74 6,517,620

10239,417,197

45,934,817

Source: Mectizan Program Notes, Isssue 15, May 1996, Mectizan Donation Program

37

Table 2. Contributions of Major Actors to Ivermectin Development

TDR Merck OCP AcademicInstitutions

Governments of Endemic Countries

Mectizan Expert

Committee

NGOs WorldBank74

Discovery

+ ++ - + - - - -

Clinical Trials

++ ++ ++ ++ + - - -

Registration

- ++ - - - - - -

Production

- ++ - - - - - -

Pricing

++ ++ + - - - - -

Distribution

+ ++ + + ++ ++ ++ +

Program Implementation

++ + ++ + ++ ++ ++ ++

++: Significant contributions + : Moderate contributions - : Negligible contribution

74The World Bank’s contributions that are presented in this table represent the Bank’s role outside its status as a co-sponsor and a member of top management of TDR.

38